tbuckley/cabot-search huggingface dataset:
Immunological correlatives of durable responses and survival benefit for patients with cervical cancer in a trial of combined chemotherapy and immune therapy.
Authors: Amanda M Honan, Rosa P Castillo, Melissa N Castillo, Shannon J Saigh, Xiaodong Cai, Zhibin Chen, Marilyn Huang
Journal: Journal of Clinical Oncology (2022)

5537 Background: Recurrent, metastatic, or persistent cervical cancer is largely an incurable disease due to lack of effective therapies. New treatment strategies are needed to provide long-term anti-tumor responses. We sought to gain insight into the immune pathways contributing to treatment response to immunotherapy. Methods: Fourteen patients with recurrent, persistent, or metastatic cervical cancer were enrolled in a single-arm phase II clinical trial (NCT03367871) with the combination of chemotherapy, bevacizumab and pembrolizumab regardless of tumor PD-L1 status. We designed a 40-color full spectrum flow cytometry panel to profile the protein markers of immune cells in peripheral blood mononuclear cells (PBMCs) at the single cell level to assess immunological correlates in blood with patients' anti-tumor responses. Results: In this trial with a cohort of predominantly Black and Hispanic patients (93%), 50% had durable responses to a combination therapy, and no difference was observed in the combined PD-L1 score (CPS) between responders and non-responders. With 40-color flow cytometry multiplex assays, we detected several differences between the non-responders and responders within the B and T cell populations. Within the B cell population, we observed a significant increase in the HLA + CD200 hi B cells, a potentially suppressive cell subset, within the non-responders while among the responders we observed an increase in the number of HLA + CD200 lo B cells. This HLA + CD200 lo subset was mainly composed of IgD - CD27 - memory B cells, a population suggested to have effector function. Moreover, the HLA + CD200 hi B cell population contained a higher percentage of PD-L1 expressing cells than the HLA + CD200 lo population, further supporting the suggestion that the HLA + CD200 hi population may be an immunosuppressive subset. Within the T cell compartment, we observed an increase in the number of CD4 + CD69 + T cells, which represent an activated CD4 T cell population, in the responder group compared to the non-responder group. The number of activated CD4 + T cells was observed to correlate (r = 0.5) with the HLA + CD200 hi B cell subset. Conclusions: This study identified novel immunological correlates in peripheral blood that were associated with durable antitumor responses and survival benefit for cervical cancer patients. These results suggest a role for T-B collaboration in effective antitumor immunity induced by combination of chemotherapy and immune therapy against cervical cancer. Clinical trial information: NCT03367871.
<i>GATA6</i> amplification is associated with improved survival of <i>TP53</i>-mutated pancreatic cancer.
Authors: Jung-In Yang, Taehoon Ha, Edward Zhou, Chris Tzanavaris, Astrid Deschênes, Jeff Boyd, Christopher Hollweg, Xinhua Zhu, Daniel King
Journal: Journal of Clinical Oncology (2022)

e16285 Background: Recent investigation in pancreatic adenocarcinoma (PDAC) demonstrates an association of molecular subtype with chemosensitivity and prognosis. TP53 and GATA6 are two genes independently associated with worse survival in PDAC. Here, we evaluated treatment outcome by genetic alterations of TP53 and GATA6 among patients with pancreatic cancer across New York’s largest health care system. Methods: This is a retrospective analysis of patients at Northwell Health diagnosed with PDAC between 2014 to 2021. Surgical status was used to segregate patients into two groups: resected and unresected. TP53 and GATA6 mutation status was compared for disease-free survival (DFS) (resected) or progression-free survival (PFS) (unresected), and for overall survival (OS). Additionally, patient survival by type of chemotherapy administered was evaluated. The Kaplan–Meier method was used to determine overall survival (OS), and the Wilcoxon test was used to compare survival curves. Results: Tumor mutational profiling data were available for 129 patients. TP53 mutations were found in 105 patients (81.4%), GATA6 amplifications were found in 18 patients (14.0%), and 16 patients had both mutations. TP53 mutations were associated with a worse OS compared to the wild-type TP53 population (n = 24) (median OS 22.7 months, 95% CI 12.5 to 41.1, vs. 44.3 months, 95% CI 24.5 to 80.3, HR 1.97, p = 0.048). Among patients with a TP53 mutation, a survival advantage was observed in those who had a GATA6 amplification compared to those who did not (median OS 25.5 months, 95% CI 10.9 to 44.6, vs. 22.1 months, 95% CI 12.6 to 51.5, HR 1.68, p = 0.038). In patients with unresected PDAC, the survival advantage of GATA6 amplification within TP53 mutated group was more prominent than the absence of the amplification (median OS 23.8 months, 95% CI 10.0 to 56.5, n = 12 vs. 10.5 months, 95% CI 4.4 to 24.8, n = 55, HR 0.52, p = 0.008). In the TP53 mutation group, among 33 patients who received Gem/NabP as the first-line chemotherapy, patients with GATA6 amplification (n = 8) had significantly improved survival compared to those without GATA6 amplification (n = 25) (mean OS 23.1 months, 95% CI 8.5 to 63.0, vs. 9.4 months, 95% CI 3.44 to 26.6, HR 0.51, p = 0.027). Conclusions: Genetic mutations in TP53 were associated with shorter OS than wild-type TP53. Contrary to our initial expectation that co-mutation would be associated with even worse survival, we found that GATA6 amplification appeared to attenuate poor prognosis observed in TP53-mutant patients. Additionally, GATA6 amplification may be a predictive marker for better responses to Gem/NabP chemotherapy.
Treatment facility: Effects on stage IV osteosarcoma survival.
Authors: Amanda Furtmann, Vincent Eaton, Peter T. Silberstein, Connor Tupper
Journal: Journal of Clinical Oncology (2022)

e23501 Background: Osteosarcoma is a malignant, bone-forming tumor that makes up approximately 20% of bone cancers. Osteosarcoma has an overall 5-year survival of 68%, so to see significant changes in survival, this study looks only at Stage IV osteosarcoma. Osteosarcoma is most commonly treated with a combination of chemotherapy and surgery, but no studies have been conducted to investigate the facility type at which treatment is received and its effect on survival outcomes. The goal of this study is to investigate the survival of patients with stage IV osteosarcoma based on treatment facility type. Methods: There were 1,634 patients with stage IV osteosarcoma identified in the National Cancer Database (NCDB), with 657 including data on facility type. SPSS version 27 was used to generate both descriptive statistics regarding demographics and Kaplan-Meier curves to determine the impact treatment facility type has on overall survival. Results: Stage IV osteosarcoma was more common in males (59.5%) and white race (77%) with 55.4% receiving treatment at academic centers, 22.5% at comprehensive community programs, 16.9% at integrated cancer programs, and 5.2% at community cancer programs. Patients on Medicare also demonstrated a decreased overall survival when compared to all other insurance types (p &lt; 0.001). In stage IV osteosarcoma patients, there were statistically significant differences in survival outcomes when comparing each facility type to each other (with p values all &lt; 0.05), except for the comparison between comprehensive community cancer programs and integrated network cancer programs. Patients who received treatment at academic/research programs demonstrated the best overall survival with a median of 7.29 months when compared to community center programs, comprehensive community cancer programs, and integrated network programs (with p values of &lt; 0.001, 0.046, and 0.03, respectively). Patients treated at academic research programs were more likely to be white males with private insurance or Medicare. Conclusions: Patients treated at academic centers for stage IV osteosarcoma had better survival outcomes compared to those treated at nonacademic facilities. These patients were more likely to be white, insured individuals. African Americans and Medicare patients were associated with increased risk of mortality from stage IV osteosarcoma. Future studies can be done with multivariate analyses to determine other variables that may affect outcomes in this patient population.[Table: see text]
Artificial intelligence-powered pathology image analysis merged with spatial transcriptomics reveals distinct TIGIT expression in the immune-excluded tumor-infiltrating lymphocytes.
Authors: Gahee Park, Sanghoon Song, Sukjun Kim, Sangheon Ahn, Hyunjoo Kim, Jaegeun Lee, Juneyoung Ro, Woomin Park, Taiwon Chung, Cholmin Kang, Chunggi Lee, Huijeong Kim, Jisoo Shin, Seungje Lee, Eunji Baek, Sumin Lee, Melody SeungHui Seo, Hyojung Choi, Donggeun Yoo, Chan-Young Ock
Journal: Journal of Clinical Oncology (2022)

2570 Background: TIGIT is a promising emerging immunotherapeutic target. However, the specific sources of TIGIT expression within the tumor microenvironment are largely unknown. Here, we present an AI-powered spatial tumor-infiltrating lymphocyte (TIL) analyzer, Lunit SCOPE IO, to integrate image analysis from whole slide images with single-cell molecular profiling. Methods: We used The Cancer Genome Atlas (TCGA) RNA expression data across 23 cancer types (n=6,930). Lunit SCOPE IO was developed, trained, and validated based on &gt;17k H&amp;E whole-slide images, to segment cancer area (CA) and cancer-associated stroma (CS) and to detect tumor cells and TILs. The intra-tumoral TIL, stromal TIL, and tumor cell purity (TCP) in the CA+CS area were calculated. The public spatial transcriptomics (ST) dataset for breast cancer was downloaded from the 10X Visium web page. Lunit SCOPE IO was applied to the associated H&amp;E WSIs to match distinct TIGIT expression to single cells identified in the WSIs. Results: TIGIT was highly expressed in TGCT (3.45±0.11; median±SEM), LUAD (3.07±0.05), and HNSC (2.89±0.06), and was highly enriched in samples with microsatellite instability-high or tumor mutational burden-high (≥ 10/Mb) compared to those without them (fold change = 1.30, p &lt; 0.001). At a macroscopic, bulk-level in the TCGA dataset, TIGIT expression was positively correlated with intra-tumoral TIL density (R=0.37, p&lt;0.001) and stromal TIL density (R=0.42, p&lt;0.001), but it was negatively correlated with TCP (R=-0.27, p&lt;0.001). Lunit SCOPE IO analyzed the images from ST analysis and calculated intra-tumoral TIL, stromal TIL, and TCP of each region of interest, containing 2 (IQR 0-7) cells. Interestingly, at a microscopic, cell-level, TIGIT expression was still higher in areas of enriched stromal TIL (P &lt; 0.001) and lower in tumor cell-dense areas, but it was not significantly correlated with enriched intra-tumoral TIL areas, meaning that TIGIT expression is likely derived from the excluded TILs in the CS area. Conclusions: Interactive analysis of spatial transcriptomics with AI-powered pathology image analysis revealed that TIGIT expression in the tumor microenvironment is exclusive to confined areas with stromal TIL enrichment, reflecting the exclusion of TIL from the tumor nest. [Table: see text]
STAR-TREC phase II: Can we save the rectum by watchful waiting or transanal surgery following (chemo)radiotherapy versus total mesorectal excision for early rectal cancer?
Authors: Simon Parkinson Bach, Johannes H.W. de Wilt, Femke Peters, Karen-Lise Garm Spindler, Ane L Appelt, Mark Teo, Victoria Homer, Natalie Louise Abbott, Ian Geh, Stephan Korsgen, Issam Al-Najami, Anouk J.M. Rombouts, Peter Christensen, Alexandra Gilbert, Leyre Navarro-Nuñez, Philip Quirke, Nicholas West, Gunnar Baatrup, Corrie Marijnen, David Sebag-Montefiore
Journal: Journal of Clinical Oncology (2022)

3502 Background: No randomised trials have compared non-operative organ preservation (OP) therapy for early-stage rectal cancer versus standard of care (SoC) using total mesorectal excision (TME) alone. STAR-TREC evaluated the feasibility of recruiting to a study comparing contrasting OP therapies, optimised for treatment of early tumours, versus SoC. Methods: STAR-TREC was a prospective, randomised, open-label, feasibility study in the UK, Netherlands and Denmark. Patients with biopsy proven adenocarcinoma of the rectum, staged ≤mrT3b N0 M0, ≤40mm diameter, ECOG 0-1 were randomised in a 1:1:1 ratio to TME, OP via mesorectal short-course radiotherapy (5x5 Gy), or OP via mesorectal chemo-radiotherapy (25x2 Gy + capecitabine) (Peters FP et al. Mesorectal radiotherapy for early stage rectal cancer: A novel target volume. Clin Transl Radiat Oncol 2020; 21: 104-11). Standardised response assessment classified OP cases as complete response for no further treatment, partial response for transanal endoscopic microsurgery or poor response for TME by 20 weeks. Surveillance following OP consisted of 3-monthly endoscopy/MRI. All cases had CT thorax/abdomen/pelvis at 24 months (m). The primary outcome was recruitment rate over 2 years, with randomisation of 120 international cases calculated as sufficient to support a phase III trial. Secondary outcomes included acute toxicity, stoma and OP rates at 12m, disease free survival (DFS) and non-regrowth DFS (NRDFS) at 24m and EORTC QLQ-C30 summary score at 12 and 24m. Phase II analysis was pre-specified, approved by the data monitoring committee conditional upon grouping of OP arms to inform phase III design, without prejudicing the outcome (STAR-TREC Phase III protocol. Colorectal Disease 2022). Results: Recruitment endpoints were met on 28 Oct 2019. Key secondary outcomes are tabulated by intention to treat. No 6-month mortality occurred. Conclusions: OP pathways optimised for early tumours reduce acute surgical morbidity without introducing substantial radiation toxicity to achieve OP in 60% with no increase in NRDFS at 24m compared to SoC. Overall quality of life was evenly matched. STAR-TREC phase III will determine the optimal strategy for achieving OP (STAR-TREC Phase III protocol. Colorectal Disease 2022). Clinical trial information: NCT02945566. [Table: see text]
Photodynamic therapy for early cervical cancer.
Authors: Viktoria A. Ivanova, Vera P. Nikitina, Ekaterina V. Verenikina, Oksana E. Zhenilo, Anna Yu Ardzha
Journal: Journal of Clinical Oncology (2022)

e17528 Background: Photodynamic therapy (PDT), with its high efficiency and selective impact on tumor cells without damaging healthy tissues, is an organ-sparing treatment preserving the anatomy and function of the cervix. Preservation of the reproductive function is the most significant criterion for the efficacy of an organ-sparing treatment. The purpose of this study was to evaluate the efficacy of PDT for early cervical cancer. Methods: PDT results were studied in 74 patients aged 18-40 years with early cervical cancer. The patients were divided into 3 groups depending on the type of transformation zone (TZ), the degree of invasion and the tumor site: group 1 - 36 patients with preinvasive cancer in the exocervix (TZ type I-II); group 2 - 34 patients with preinvasive cancer in the endocervix (TZ type III); group 3 - 4 patients with microinvasive cancer T1a1N0M0 with invasion of no more than 1 mm as an alternative to surgical intervention. Infection with high-risk genotypes of HPV (16, 18, 31, 33, 35, 45, 56) was detected with PCR in 62 (84%) women. All patients received PDT with the semiconductor Latus laser up to 3 W, a single-use diffusing fiber for the exocervix irradiation and a single-use cylindrical diffusing fiber for tumors in the cervical canal. Chlorin e6 was used as a photosensitizer. The efficiency criteria included the normalization of the colposcopic and morphological picture, and the HPV elimination confirmed by the PCR test. 4 to 8 procedures were required to restore the normal layer of stratified squamous epithelium. Results: PDT was followed by direct photocoagulation necrosis caused by the destruction of cellular structures, and ischemic necrosis as a result of damage and destruction of the microvasculature of the initial tumor changes in the cervical epithelium. Epithelialization of the cervix was completed by days 35-40. Normal morphological picture was observed in 96% of patients in group 1 and in 95% of patients in group 2; all patients in group 3 had a pronounced positive response. PCR 3 months after PDT showed a positive HPV reaction in 5.1% of patients. No negative changes in the cytogram were detected 6 and 12 months after PDT. The maximum follow-up period has lasted for 5.1 years. No relapses of the disease have been registered. During the follow-up period, four patients with preinvasive cancer and one patient with microinvasive cancer successfully gave birth to healthy children. Conclusions: PDT is an alternative treatment for precancerous and early malignant tumors of the cervix; it preserves the anatomical and functional integrity of the organ, which is important for the female reproductive function. The results of the study allow recommending PDT in the treatment of early cervical cancer.
Prognostic factors for patients with advanced renal cell carcinoma (aRCC) in the era of first-line (1L) treatment with immune checkpoint inhibitors (ICIs).
Authors: Charlene Mantia, Opeyemi Jegede, Meredith M. Regan, Michael B. Atkins, David F. McDermott
Journal: Journal of Clinical Oncology (2022)

4544 Background: The most commonly used prognostic models in aRCC, the Memorial Sloan-Kettering Cancer Center (MSKCC) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores, were developed when cytokines and VEGF targeted monotherapies were standard of care, respectively. aRCC 1L treatment now includes combination therapy with 2 ICIs or ICI+VEGF receptor inhibitor. Re-evaluation of the MSKCC and IMDC prognostic models in the era of ICI therapy and identification of additional prognostic factors are overdue. Methods: Data from 1052 patients with aRCC treated on the CheckMate-214 (CM214) clinical trial with 1L nivolumab/ipilimumab (NIVO/IPI) or sunitinib (SUN) were analyzed retrospectively at median follow-up 5 yrs. For each treatment group, multivariable Cox model hazard ratios (HR) were compared to the published MSKCC and IMDC model HRs. Discrimination (c index) was assessed based upon the continuous scores obtained as the weighted combination of regression parameters from the published MSKCC &amp; IMDC models. Results: KPS &lt; 80% remained highly prognostic in both treatment groups (HRs &gt; 2.5). With the exception of high calcium, the other factors of time from dx to treatment &lt; 1 yr, hemoglobin &lt; lower limit of normal (LLN), neutrophils &gt; upper limit of normal (ULN), platelets &gt; ULN and LDH &gt; 1.5xULN consistently retained prognostic value for SUN (HRs ≥ published model HRs) but had diminished prognostic value for NIVO/IPI (each HR &lt; published model HR). High calcium had diminished prognostic value for SUN and retained prognostic value for NIVO/IPI. The c-indices for discrimination were 0.61 and 0.64 for the MSKCC model in the NIVO/IPI and SUN treatment groups, respectively, and were 0.63 and 0.67 for the IMDC model in the NIVO/IPI and SUN treatment groups compared to reported IMDC c-index of 0.73 (Heng 2009). (Table) Conclusions: The prognostic ability of the MSKCC and IMDC risk models is reduced with combination ICI treatment. Evaluation of additional prognostic factors and development of new risk scores are needed and this work is ongoing. [Table: see text]
The frequency of second primary malignancies and colonic polyps in Lynch syndrome with MSI tumors following immune checkpoint blockade.
Authors: Emily Harrold, Zalak Patel, Anna Maio, Andrea Cercek, Rona Yaeger, Neil Howard Segal, Diane Lauren Reidy, Eileen Mary O'Reilly, Avni Mukund Desai, Maria Isabel Carlo, Alicia Latham, Ying L Liu, Diana Mandelker, Arnold Markowitz, Kenneth Offit, Jinru Shia, Luis A. Diaz, Zsofia Kinga Stadler
Journal: Journal of Clinical Oncology (2022)

10505 Background: Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair genes and is characterized by microsatellite instability (MSI) status of associated tumors. MSI sensitizes tumors to immune checkpoint inhibition (ICI). The incidence of second primary malignancies and colonic polyps in LS patients with MSI tumors following ICI has not been evaluated. Methods: The Memorial Sloan Kettering LS database was queried for all patients with cancer who received ≥1 cycle of ICI using an IRB approved protocol. LS was confirmed by presence of a germline pathogenic/likely pathogenic alteration in a DNA mismatch repair gene ( MLH1, MSH2, MSH6, PMS2, EPCAM). Tumor and matched normal DNA sequencing was performed via MSK-IMPACT, an IRB approved protocol (NCT01775072). MSI status was assessed using MSIsensor. Results: At our center, 131 patients with LS received ICI mostly (73.3%) in the context of metastatic cancer. While 108 patients received ICI for an MSI tumor, 23 LS patients received ICI for a MSS (Microsatellite Stable) tumor (4 hepatobiliary, 3 colorectal, 3 CNS, 2 endometrial, 2 gastroesophageal, 2 renal, 2 sarcoma, 5 other). Five patients (3.8%) developed ≥1 second primary malignancy while on or following ICI comprised of an MSI small bowel adenocarcinoma, MSI upper tract urothelial cancer, 2 MSS prostate cancers, MSS HCC and MSI sebaceous neoplasm; 1 patient developed both MSS prostate cancer and MSI urothelial cancer on ICI. All five patients’ primary malignancy was MSI. Only a minority of patients underwent surveillance colonoscopies post completion of ICI (31.3%, (41/131)). Of these 41, nine (22%, (9/41)) were identified to have polyps including 8 tubular adenomas and 1 tubulo-villous adenoma. Median time to development of a polyp was 22 months (95% CI 16.82-27.18) from last colonoscopy and 13 months (95% CI 4-25 months) from last ICI. Notably amongst the 23 LS patients whose tumors were MSS, 14 had progression on ICI. Conclusions: Herein, we demonstrate that in LS-patients in receipt of ICI for cancer treatment, the risk of a second primary cancer and polyps remain high following treatment with ICI. Biological mechanisms underlying immune escape warrant further investigation. Surveillance strategies should be continued for LS patients post ICI.